title: Comparison of vascular growth factors in the murine brain reveals placenta growth factor as prime candidate for CNS revascularization.
abstract: Vascular bypass procedures in the central nervous system (CNS) remain technically challenging, hindered by complications and often failing to prevent adverse outcome such as stroke. Thus, there is an unmet clinical need for a safe and effective CNS revascularization. Vascular endothelial growth factors (VEGFs) are promising candidates for revascularization; however, their effects appear to be tissue-specific and their potential in the CNS has not been fully explored. To test growth factors for angiogenesis in the CNS, we characterized the effects of endothelium-specific growth factors on the brain vasculature and parenchyma. Recombinant adeno-associated virus (AAV) vectors encoding the growth factors were injected transcranially to the frontoparietal cerebrum of mice. Angiogenesis, mural cell investment, leukocyte recruitment, vascular permeability, reactive gliosis and neuronal patterning were evaluated by 3-dimensional immunofluorescence, electron microscopy, optical projection tomography, and magnetic resonance imaging. Placenta growth factor (PlGF) stimulated robust angiogenesis and arteriogenesis without significant side effects, whereas VEGF and VEGF-C incited growth of aberrant vessels, severe edema, and inflammation. VEGF-B, angiopoietin-1, angiopoietin-2, and a VEGF/angiopoietin-1 chimera had minimal effects on the brain vessels or parenchyma. Of the growth factors tested, PlGF emerged as the most efficient and safe angiogenic factor, hence making it a candidate for therapeutic CNS revascularization.
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Emília Ilona
authors.initials: EI
authors.lastname: Gaál
authors.forename: Tuomas
authors.initials: T
authors.lastname: Tammela
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisimov
authors.forename: Serge
authors.initials: S
authors.lastname: Marbacher
authors.forename: Petri
authors.initials: P
authors.lastname: Honkanen
authors.forename: Georgia
authors.initials: G
authors.lastname: Zarkada
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Leppänen
authors.forename: Turgut
authors.initials: T
authors.lastname: Tatlisumak
authors.forename: Juha
authors.initials: J
authors.lastname: Hernesniemi
authors.forename: Mika
authors.initials: M
authors.lastname: Niemelä
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000254:growth & development / Q000378:metabolism; D002490:Central Nervous System / Q000098:blood supply*; D016543:Central Nervous System Neoplasms / Q000209:etiology / Q000235:genetics; D002548:Cerebral Revascularization; D004660:Encephalitis / Q000209:etiology / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006391:Hemangioma / Q000209:etiology / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000235:genetics; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000009:adverse effects / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000009:adverse effects / Q000235:genetics
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D000072483:Placenta Growth Factor